The story starts by introducing 17-year old (initially 16 in the manga) high school student Jimmy Kudo (Shin'ichi Kudo) who is a genius savant, and his childhood friend and crush, Rachel Moore (Ran Mori). Jimmy treats Rachel to a trip to a theme park named "Tropical Land" and encounters a murder. After easily solving the case and showing off his detective skills, he notices two mysterious men wearing black. Telling Rachel to go home without him, he tracks the men to a meeting place and witnesses an illegal deal. However, one of the men in black (known only as Gin), notices him and knocks him out. Instead directly killing him, the two men in black decide to give him an untested experimental poison named Apotoxin-4869 (APTX4869), because there are still many police around from the previous case. The poison was supposed to not only kill Jimmy, but also leave no trace of itself in his body. However, Jimmy wakes to find that he is still alive, but has now been shrunken, and his age reverted back to that of about his six-year-old self.
Following the advice of Dr. Herschel Agasa (Dr. Hiroshi Agasa), Jimmy decides to hide his real identity, lest the men in black find out that he is alive. When Rachel asks for his name, Jimmy spots books by Arthur Conan Doyle and Edogawa Rampo and comes up with the name "Conan Edogawa". Agasa says that "Conan" is a relative of his, but that he is too busy to take care of a young child, and suggests that Conan go to live with Rachel, and both Conan and Rachel agree. Conan feels that by living with a detective, he may be able to amass clues that would lead him to the people who poisoned him.
However, Rachel's father, Richard Moore (Kogoro Mori) is an inept detective and Conan almost always has to solve mysteries in his stead, while he gets all the credit. As Conan appears to be just a boy, police do not pay much attention to him. Conan instead uses Detective Moore by putting him to sleep with an "anesthesia dart-watch", propping him up so the others can't see his that his mouth is not moving, then hiding nearby and pretending to be Moore by using a voice changer disguised as a bow tie. These gadgets and more are made by Dr. Agasa. However, when this method is not an option, he points things out to Richard which help him solve the case.
To maintain his cover, Conan goes to Titan elementary school (Japanese: Teitan Elementary School ) and has made friends with three children in his class; George Kaminski (Genta Kojima), Mitch Tennison (Mitsuhiko Tsuburaya) and Amy Yeager (Ayumi Yoshida) who form the self-styled "Junior Detective League" (Detective Boys in the Japanese anime and manga). Although Conan feels profoundly self conscious playing with them given his true age, the foursome have numerous adventures of their own and the trio have proved capable assistants to the detective for their age.
Jimmy was eventually able to find out that Gin was working for a huge super-secret international crime syndicate, known as the Black Organization. In addition to Gin, other major members and operatives of the Black Organization that appear later in the story include his partner Vodka, Vermouth, Kir, Chianti, Korn, and a mysterious "boss" who has only been mentioned so far.
Later on in the series, Jimmy meets with his parents, Booker (Yusaku) and Vivian (Yukiko) Kudo along with Harley Hartwell (Heiji Hattori), a rival detective from Osaka who later becomes his good friend, and Harley's childhood friend Kazuha Toyama. Another recurring character is the gentleman thief known as the Phantom Thief Kid (Kaito Kid) , who also appears in Aoyama's other manga, Magic Kaito. Aside from the Black Organization members, he is the only person that Conan seems unable to catch, and neither realize that they are both after the same "bad guys".